Modulating Glycolysis to Improve Cancer Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2606 - 2606

Published: Jan. 30, 2023

Cancer cells undergo metabolic reprogramming and switch to a ‘glycolysis-dominant’ profile promote their survival meet requirements for energy macromolecules. This phenomenon, also known as the ‘Warburg effect,’ provides advantage cancer make tumor environment more pro-cancerous. Additionally, increased glycolytic dependence promotes chemo/radio resistance. A similar is shown by immune in microenvironment, inducing competition between tumor-infiltrating over nutrients. Several recent studies have that targeting enhanced glycolysis promising strategy them susceptible treatment with other conventional modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, photodynamic therapy. Although several strategies been developed of are different stages pre-clinical clinical evaluation, there still lack effective specifically target cell improve efficacy. Herein, we reviewed our current understanding role how this phenomenon could be potential efficacy

Language: Английский

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Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 10037 - 10037

Published: Sept. 2, 2022

Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined a “metabolically abnormal system”. Carbohydrates metabolically reprogrammed by its metabolizing and catabolizing enzymes in such cells. Normal acquire their energy from oxidative phosphorylation, while glycolysis, known the “Warburg effect”. Energy–metabolic differences easily found growth, invasion, immune escape anti-tumor drug resistance The pathway carried out multiple enzymatic steps yields two pyruvate molecules one glucose (Glc) molecule orchestral reaction enzymes. Uncontrolled or abnormally activated observed metabolism with enhanced levels glycolytic proteins activities. In effect”, tumor utilize supplied lactic acid-based fermentative operated glycolysis-specific hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, isozyme type M2 (PKM2), dehydrogenase (PDH), PDH lactate dehydrogenase. They related to flux. key involved directly linked oncogenesis resistance. Among metabolic enzymes, PKM2, PGK1, HK, keto-HK-A nucleoside diphosphate also have protein Because glycolysis-generated not enough, cell-favored produce low ATP level seems be non-efficient for growth self-protection. Thus, Warburg effect still attractive phenomenon understand favored cancer. If basic properties effect, including genetic mutations signaling shifts considered, anti-cancer therapeutic targets can raised. Specific therapeutics targeting aerobic hypoxic microenvironments been developed kill present review deals tumor-specific revisited viewpoint recent progress.

Language: Английский

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Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 28, 2023

Abstract Rheumatoid arthritis (RA) is a common chronic inflammatory disorder that usually affects joints. It was found roburic acid (RBA), an ingredient from anti-RA herb Gentiana macrophylla Pall., displayed strong anti-inflammatory activity. However, its medical application limited by hydrophobicity, lack of targeting capability and unclear functional mechanism. Here, we constructed pH responsive dual-target drug delivery system hitchhiking RBA (RBA-NPs) targeted both CD44 folate receptors, investigated pharmacological In rat RA model, the nanocarriers effectively delivered to sites significantly enhanced therapeutic outcomes compared with free RBA, as well strongly reducing cytokine levels promoting tissue repair. Following analysis revealed M1 macrophages in joints were reprogrammed M2 phenotype RBA. Since balance pro- play important roles maintaining immune homeostasis preventing excessive inflammation RA, this reprogramming likely responsible for effect. Furthermore, RBA-NPs drove M1-to-M2 phenotypic switch down-regulating glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway. Thus, our work not only developed remarkably improved efficiency but also identified potential molecular target reversely reprogram though energy metabolism regulation.

Language: Английский

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Engineering lactate-modulating nanomedicines for cancer therapy

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(3), P. 973 - 1000

Published: Jan. 1, 2023

Lactate in tumors has long been considered "metabolic junk" derived from the glycolysis of cancer cells and utilized only as a biomarker malignancy, but is presently believed to be pivotal regulator tumor development, maintenance metastasis. Indeed, lactate can "fuel" for energy supply functions signaling molecule, which actively contributes progression, angiogenesis, immunosuppression, therapeutic resistance, etc., thus providing promising opportunities treatment. However, current approaches regulating homeostasis with available agents are still challenging, mainly due short half-life, low bioavailability poor specificity these their unsatisfactory outcomes. In recent years, modulation nanomedicines have emerged charming efficient strategy fighting cancer, play important roles optimizing delivery lactate-modulating more precise effective Integrating specific diverse may overcome intrinsic restrictions different modalities by remodeling pathological microenvironment achieving enhanced therapy. this review, most advances engineering functional that modulate therapy summarized discussed, fundamental mechanisms benefits various therapeutics elucidated. Finally, challenges perspectives emerging anti-tumor field highlighted.

Language: Английский

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Inhibiting Angiogenesis by Anti-Cancer Saponins: From Phytochemistry to Cellular Signaling Pathways

Metabolites, Journal Year: 2023, Volume and Issue: 13(3), P. 323 - 323

Published: Feb. 22, 2023

Saponins are one of the broadest classes high-molecular-weight natural compounds, consisting mainly a non-polar moiety with 27 to 30 carbons and polar containing sugars attached sapogenin structure. found in more than 100 plant families as well marine organisms. have several therapeutic effects, including their administration treatment various cancers. These compounds also reveal noteworthy anti-angiogenesis effects critical strategies for inhibiting cancer growth metastasis. In this study, comprehensive review is performed on electronic databases, PubMed, Scopus, ScienceDirect, ProQuest. Accordingly, structural characteristics triterpenoid/steroid saponins anti-cancer were highlighted, focusing anti-angiogenic related mechanisms. Consequently, saponins, expression genes vascular endothelial factor (VEGF) hypoxia-inducible 1-α (HIF-1α) two main mechanisms triterpenoid steroidal saponins. The inhibition inflammatory signaling pathways that stimulate angiogenesis, such pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), phosphoinositide 3-kinases/protein B (PI3K/Akt), other Furthermore, activity was closely binding site sugar moiety, type number monosaccharide units, presence some functional groups aglycone Therefore, suitable candidates by which extensive pre-clinical clinical trial studies recommended.

Language: Английский

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Hypoxia conduces the glioma progression by inducing M2 macrophage polarization via elevating TNFSF9 level in a histone-lactylation-dependent manner

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 327(2), P. C487 - C504

Published: July 16, 2024

Hypoxia is a critical factor contributing to poor prognosis and challenging glioma therapy. Previous studies have indicated that hypoxia drives M2 polarization of macrophages promotes cancer progression in various solid tumors. However, the more complex diverse mechanisms underlying this process remain be elucidated. Here, we aimed examine functions gliomas preliminarily investigate macrophage caused by hypoxia. We found significantly enhances malignant phenotypes U87 U251 cells regulating glycolysis. In addition, mediated accumulation glycolysis product [lactic acid (LA)], which subsequently absorbed induce its polarization, reverted both inhibitor silenced monocarboxylate transporter (MCT-1) macrophages, indicating associated with promotion Interestingly, also LA upon uptake upregulates H3K18La expression tumor necrosis superfamily member 9 (TNFSF9) histone-lactylation-dependent manner based on results chromatin immunoprecipitation sequencing (ChIP seq) enrichment analysis. Subsequent vitro vivo experiments further TNFSF9 facilitated progression. Mechanistically, hypoxia-mediated taken up then induces via MCT-1/H3K18La signaling, thus facilitating gliomas.

Language: Английский

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Role of lactate and lactate metabolism in liver diseases (Review)

International Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 54(1)

Published: May 20, 2024

Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in presence oxygen to produce lactate) it considered metabolic waste product. At present, lactate not only recognized as substrate that provides energy, but also signaling molecule regulates cellular functions under pathophysiological conditions. Lactylation, post‑translational modification, involved development various diseases, including inflammation tumors. Liver disease major health challenge worldwide. In normal liver, there net uptake caused by gluconeogenesis, exhibiting higher clearance rate compared with any other organ. Therefore, abnormalities metabolism lead liver disease, metabolism‑related genes used for predicting prognosis disease. Targeting production, regulating transport modulating lactylation may potential treatment approaches However, currently systematic review summarizes role diseases. present review, diseases fibrosis, non‑alcoholic fatty acute failure hepatocellular carcinoma summarized aim provide insights future research.

Language: Английский

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Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Sept. 19, 2022

Cancer cells and immune all undergo remarkably metabolic reprogramming during the oncogenesis tumor immunogenic killing processes. The increased dependency on glycolysis is most typical trait, profoundly involved in microenvironment cancer immunity regulation. However, how to best utilize glycolytic targets boost anti-tumor improve immunotherapies are not fully illustrated. In this review, we describe remodeling of various within (TME) deleterious effects limited nutrients acidification derived from enhanced immunological capacity. Moreover, elucidate underlying regulatory mechanisms reprogramming, including crosstalk between pathways checkpoint signaling. Importantly, summarize potential glycolysis-related that expected immunotherapy benefits. Our understanding will be instrumental for future therapeutic regimen development.

Language: Английский

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A new strategy for osteoarthritis therapy: Inhibition of glycolysis

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 10, 2022

Osteoarthritis (OA) is a common degenerative disease of the joints. It primarily caused by age, obesity, mechanical damage, genetics, and other factors, leading to cartilage degradation, synovial inflammation, subchondral sclerosis with osteophyte formation. Many recent studies have reported that glycolysis disorders are related lead OA. There close relationship between Because their hypoxic environment, chondrocytes highly dependent on glycolysis, primary energy source for chondrocytes. Glycolysis plays vital role in OA development. In this paper, we comprehensively summarized abnormal expression glycolytic enzymes OA, including Hexokinase 2 (HK2), Pyruvate kinase (PKM2), Phosphofructokinase-2/fructose-2, 6-Bisphosphatase 3 (PFKFB3), lactate dehydrogenase A (LDHA), discussed potential application treating Finally, natural products can regulate pathway were summarized. Targeting glucose transporters rate-limiting may play an essential

Language: Английский

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Natural compounds as lactate dehydrogenase inhibitors: potential therapeutics for lactate dehydrogenase inhibitors-related diseases

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 17, 2023

Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present various cells throughout the body. Its diverse physiological functions encompass glycolysis, its abnormal activity associated with numerous diseases. Targeting LDH has emerged as vital approach drug discovery, leading to identification of inhibitors among natural compounds, such polyphenols, alkaloids, terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, toxicity must be addressed. Combining led promising outcomes preclinical studies. This review highlights promise for treating cancer, cardiovascular, neurodegenerative

Language: Английский

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